(R)-α-methyl-N-[3-[3-(trifluoromethyl)phenyl]propyl]-1-naphthalenemethane amine is known as Cinacalcet. The Cinacalcet hydrochloride has the molecular formula C22H22F3N.HCl, a molecular weight of 393.9 and the chemical structure:
The CAS number for the hydrochloride is 364782-34-3, and that of the free base is 226256-56-0.
Cinacalcet is marketed as SENSIPAR™ (Amgen, USA), and is the first drug in a class of compounds known as calcimimetics to be approved by the FDA. Cinacalcet is approved for treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis. Elevated levels of parathyroid hormone (PTH), an indicator of secondary hyperparathyroidism, are associated with altered metabolism of calcium and phosphorus, bone pain, fractures, and an increased risk for cardiovascular death.
Calcimimetics are a class of orally active, small molecules that decrease the secretion of PTH by activating calcium receptors. The secretion of PTH is normally regulated by the calcium-sensing receptor. Calcimimetic agents increase the sensitivity of this receptor to calcium, which inhibits the release of parathyroid hormone, and lowers parathyroid hormone levels within a few hours. Calcimimetics are used to treat hyperparathyroidism, a condition characterized by the over-secretion of PTH that results when calcium receptors on parathyroid glands fail to respond properly to calcium in the bloodstream. Treatment with Cinacalcet lowers serum levels of PTH as well as the calcium/phosphorus ion product, a measure of the amount of calcium and phosphorus in the blood, which, when elevated, causes harmful deposition of calcium in various parts of the body.
U.S. Pat. No. 6,011,068 discloses calcium receptor-active molecules, such as those having the general structure of Cinacalcet. U.S. Pat. No. 6,211,244 discloses calcium receptor-active compounds related to Cinacalcet and methods of making such compounds. Cinacalcet and its enantiomer may be produced by various methods, using the processes disclosed in U.S. Pat. No. 6,211,244, DRUGS OF THE FUTURE, 27 (9), 831 (2002) and U.S. Pat. No. 5,648,541.
The present invention relates to the solid state physical properties of Cinacalcet hydrochloride. These properties can be influenced by controlling the conditions under which Cinacalcet hydrochloride is obtained in solid form. Solid state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. When particles of the powdered compound do not flow past each other easily, a formulation specialist must take that fact into account in developing a tablet or capsule formulation, which may necessitate the use of glidants such as colloidal silicon dioxide, talc, starch, or tribasic calcium phosphate.
Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient's stomach fluid can have therapeutic consequences, as it imposes an upper limit on the rate at which an orally-administered active ingredient can reach the patient's bloodstream. The rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments. The solid state form of a compound may also affect its behavior on compaction and its storage stability.
The discovery of new polymorphic forms of a pharmaceutically useful compound and of processes of preparing such polymorphic forms provides opportunities to improve the performance characteristics of a pharmaceutical product. Such discoveries enlarge the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic. Thus, the present invention presents new crystalline forms of Cinacalcet HCl to the pharmaceutical sciences.